The present invention is directed to cyclic peptides that have somatostatin agonist activity, as defined by formula (I), shown and defined hereinbelow, or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising said peptides and the use thereof as a somatostatin receptor subtypes agonist. The peptides of the present invention bind selectively to the somatostatin subtype receptor 5 and elicit an agonist effect from the somatostatin subtype receptors that the peptides bind to.
Somatostatin (SRIF) is a cyclic tetradecapeptide hormone containing a disulfide bridge between position 3 and position 14 (Heiman, et al., Neuroendocrinology, 45:429-436 (1987)) and has the properties of inhibiting the release of growth hormone (GH) and thyroid-stimulating hormone (TSH), inhibiting the release of amylin, insulin and glucagon, reducing gastric secretion and neurotransmitter release. Metabolism of somatostatin by aminopeptidases and carboxypeptidases leads to a short duration of action. Because of the short half-life of the native somatostatin, various somatostatin analogs have been developed, e.g., for the treatment of acromegaly. Raynor, et al., Molecular Pharmacol. 43:838 (1993).
Five distinct somatostatin receptors have been identified and characterized. Hoyer, et al., Naunyn-Schmiedeberg's Arch. Pharmacol., 350:441 (1994). Somatostatin binds to five distinct receptor (SSTR) subtypes with relatively high and equal affinity for each subtype. Binding to the different types of somatostatin subtypes have been associated with the treatment of the following conditions and/or diseases. (“SSTR-2”) (Raynor, et al., Molecular Pharmacol. 43:838 (1993); Lloyd, et al., Am. J. Physiol. 26B:G102 (1995)) while the inhibition of insulin has been attributed to the somatostatin type-5 receptor (“SSTR-5”) (Coy, et al. 197:366-371 (1993)). Activation of types 2 and 5 have been associated with growth hormone suppression and more particularly GH secreting adenomas (Acromegaly) and TSH secreting adenomas. Activation of type 2 but not type 5 has been associated with treating prolactin secreting adenomas. Other indications associated with activation of the somatostatin subtypes are inhibition of insulin and/or glucagon and more particularly diabetes mellitus, angiopathy, proliferative retinopathy, dawn phenomenon and Nephropathy; inhibition of gastric acid secretion and more particularly peptic ulcers, enterocutaneous and pancreaticocutaneous fistula, irritable bowel syndrome, Dumping syndrome, watery diarrhea syndrome, AIDS related diarrhea, chemotherapy-induced diarrhea, acute or chronic pancreatitis and gastrointestinal hormone secreting tumors; treatment of cancer such as hepatoma; inhibition of angiogenesis, treatment of inflammatory disorders such as arthritis; retinopathy; chronic allograft rejection; angioplasty; preventing graft vessel and gastrointestinal bleeding. It is preferred to have an analog which is selective for the specific somatostatin receptor subtype responsible for the desired biological response, thus, reducing interaction with other receptor subtypes which could lead to undesirable side effects.
The peptides of formula (I) are a sub-genus encompassed by a genus of compounds described and claimed in U.S. application Ser. No. 08/855,204, filed May 13, 1997, now U.S. Pat. No. 6,262,229, issued Jul. 17, 2001 and assigned in part to the assignee of the present invention. The compounds of formula (I) of the present application are not specifically described in U.S. Pat. No. 6,262,229. It has been unexpectedly and surprisingly discovered that the compounds of formula (I) of the present invention possess somatostatin agonist activity. This is an unexpected and surprising discovery since the compounds of U.S. Pat. No. 6,262,229 were originally found to possess somatostatin antagonist activity.